This application is focused on the development of new therapeutic approaches to Alzheimer's disease (AD) that target the nuclear receptors, liver X receptors (LXRs) and peroxisome proliferator-activated receptor gamma (PPARy). We demonstrate that treatment of an aged animal model of AD (Tg2576) with LXR agonists results in the reduction of A[unreadable] peptide levels and plaque load. We show that the ability of LXR agonists to clear A[unreadable] from the brain is reliant upon ApoE. Importantly, we demonstrate an entirely novel mechanism through which ApoE facilitates the proteolytic degradation of A[unreadable] peptides. LXR activation results in the transcriptional induction of ApoE and the lipid transporter ABCA1. ABCA1 is required for the functional maturation of ApoE through its lipidation, leading to the formation of ApoE-containing HDL-like particles that are required for cholesterol and phospholipid trafficking in the brain. A[unreadable] binds to ApoE with high affinity and this interaction is governed by the lipidation status of ApoE. We show that lipidated forms of ApoE facilitate the intracellular degradation of A[unreadable] peptides by microglia through neprilysin- dependent proteolysis. Further, we demonstrate that the lipidated ApoE acts to chaperone the extracellular degradation of A[unreadable] by insulin degrading enzyme. In contrast, poorly lipidated forms of ApoE form stable, protease resistant complexes. Importantly, agonists of the related nuclear receptor PPARy can elicit similar effects and we hypothesize that PPARy participates in a positive, self reinforcing, feed back loop with LXR to stimulate ApoE lipidation and A[unreadable] clearance. These data establish a previously unrecognized action of ApoE, facilitating the proteolytic clearance of A[unreadable] from the brain that may underlie its participation in AD pathogenesis. We propose to establish the therapeutic parameters for LXR agonist treatment to prevent and to reverse the development of AD-related plaque pathology in an animal model of AD. We will validate the LXRs as a therapeutic target by examination of murine models of AD in which LXRs have been genetically inactivated. We will establish the mechanisms through which the LXRs and PPARy target genes, most prominently ApoE and ABCA1, to facilitate A[unreadable] clearance. We will test if the actions of PPARy on A[unreadable] clearance are secondary to, and reliant upon, LXR function.